Lubricating block copolymers and their use as biomimetic boundary lubricants

ABSTRACT

The invention relates to methods of lubricating biological tissue, such as joints, bone, ocular tissue, nasal tissue, tendons, tendon capsule, and vaginal tissue, by contacting the biological tissue with an effective amount of a block copolymer lubricating composition which functions at least or better than lubricin. In particular embodiments, the method is used to treat osteoarthritis. In specific embodiments, the block copolymer has an ammonium-containing polymer block and a non-ionic hydrophilic polymer block, or the copolymer has a carboxylic acid-containing polymer block and a non-acid non-ionic hydrophilic polymer block.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to provisionalapplication U.S. Ser. No. 62/403,962, filed Oct. 4, 2016, which isincorporated herein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant No.AR066667-01 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

The Sequence Listing in the ASCII text file, named as34159_7566_03_US_SequenceListing.txt of 2 KB, created on Feb. 17, 2022,and submitted to the United States Patent and Trademark Office viaEFS-Web, is incorporated herein by reference.

FIELD OF THE INVENTION

This invention generally relates to pharmaceutically acceptablelubricating compositions and their use in methods of lubricatingbiological tissue, especially joint, cartilage, and bone surfaces. Theinvention more particularly relates to polymeric compositions that mimicthe action of lubricin, and more particularly, to methods of using suchcompositions for treating a variety of conditions, such asosteoarthritis, where lubrication is especially beneficial in treatingand ameliorating the effects of the disease or condition.

BACKGROUND OF THE INVENTION

Lubricin is a glycosylated protein found in synovial fluid, plays apivotal role in joint boundary lubrication and prevention ofosteoarthritis. Lubricin reduces the coefficient of friction (COF) ofarticular cartilage in the boundary mode by as much as 70 percent(Gleghorn, J. P. et al., J. Orthop. Res. 2009, 27 (6), 77). This potentlubricating ability arises from the structure of lubricin: a centralmucin-like domain of lubricin consists of an extensively glycosylatedcore protein that attracts and retains water near the molecule; and theC-terminus of lubricin binds the protein to the cartilage surface(Zappone, B. et al., Langmuir 2008, 24 (4), 1495). This architecture iscrucial to the boundary mode lubrication of articular cartilage asdenaturation in either domain of lubricin would cause partial orcomplete loss of lubrication capacities.

Osteoarthritis (OA) afflicts over 50 million individuals in thedeveloped world and this number is expected to rise as median age andlife expectancy increase. The economic impact of osteoarthritistreatment exceeds $30 billion annually in the United States alone. Thefinancial burden, as well as other factors (i.e., quality of life, lossof labor hours, etc.) incentivizes development of more effectivetreatments.

Current treatments for osteoarthritis include non-steroidalanti-inflammatories, intra-articular corticosteroid injections, andchondroitin sulfate or glucosamine supplements. However, all of thesetreatments have little or no effect on disease progression. A morerecent approach to the treatment of OA is the intra-articular injectionof the natural synovial fluid glycosaminoglycan, hyaluronic acid (HA)(e.g., Mabuchi et al. (1994) J. Biomed. Mat. Res. 28:865-70), where HAis known to increase synovial fluid viscosity (e.g.,viscosupplementation) to reduce the coefficient of friction in thehydrodynamic mode of lubrication (e.g., Tadmor et al. (2002) J. Biomed.Mat. Res. 61:514-23). The other predominant lubrication component insynovial fluid is lubricin, a high molecular weight glycoprotein thatreduces the coefficient of friction in the boundary mode of lubrication.

In damaged cartilage, it is well known that chondrocyte production oflubricin is compromised and boundary mode lubrication is reduced.Natural lubricants, such as proteoglycan aggregates and mucins (e.g.,lubricin), keep natural surfaces hydrophilic. Intra-articular injectionof supplemental lubricin, as well as the truncated recombinant lubricinconstruct LUB:1, have been shown to slow progression of OA in rat modelsof disease (e.g., Jay et al. (2010) Arthritis Rheum. 62:2382-91;Flannery et al. (2009) Arthritis Rheum. 60:840-7). However, to date, thelarge-scale recombinant manufacture of both lubricin and LUB:1 remainschallenging owing to multiple amino acid repeats in the protein core, aswell as the high degree of glycosylation (e.g., Jay (2004) Curr. Opin.Orthop. 15:355-359; Jones et al. (2007) J. Orthop. Res. 25:283-292).There is also a separate need for an effective lubricating agent forbone in situations where direct bone-on-bone contact occurs, as mayoccur in the advanced stages of osteoarthritis. Consequently, effectivelubricating agents that could provide the same or similar boundarylubrication as lubricin or LUB:1 would be a significant advance in thefield.

SUMMARY OF THE INVENTION

The present disclosure is directed to the design, synthesis, and use ofspecialized block copolymers having a lubricin-mimetic structure andwhich provide substantial lubrication capacity under boundary modelubrication conditions. In particular embodiments, the block copolymercontains a lubrication block (e.g., M_(n)˜200 kDa) that mimicks themucin-like domain of lubricin and a smaller cartilage-binding block(e.g., M_(n)˜3 kDa) that mimicks the hemopexin-like domain. As disclosedlater on in this application, applying this type of polymer tolubricin-deficient bovine articular cartilage or bone resulted in asignificantly reduced coefficient of friction (COF) compared tountreated controls.

In one aspect, the invention is directed to block copolymers having thefollowing structure:

wherein: R¹, R², and R³ are independently selected from hydrocarbongroups having at least one and up to twelve carbon atoms; X and X′ areindependently selected from —NR′—, —O—, and a bond, wherein R′ isselected from hydrogen atom and hydrocarbon groups having at least oneand up to six carbon atoms; Y is selected from polyalkylene glycol,saccharide, and polyalcohol; subscripts a and b are independentlyintegers of at least 3; and subscript c is an integer of at least 1. Inaccordance with the laws of chemistry, the block copolymer is terminatedon each end by terminal groups, and the total positive charge ofquaternary ammonium groups in the copolymer is counterbalanced by atotal negative charge of equivalent magnitude provided by anionsassociated with the ammonium groups.

In another aspect, the invention is directed to block copolymers havingthe following structure:

wherein: X is selected from —NR′—, —O—, and a bond, wherein R′ isselected from hydrogen atom and hydrocarbon groups having at least oneand up to six carbon atoms; Y is selected from polyalkylene glycol,saccharide, and polyalcohol; R is a hydrogen atom, hydrocarbon group (R)having 1-12 carbon atoms, or a cartilage binding domain; subscripts dand e are independently integers of at least 3; and subscript f is 0 oran integer of at least 1. In the formula, the hydrogen atom on the showncarboxylic acid group is optionally replaced with a positively chargedmetal ion or positively charged organic group. In accordance with thelaws of chemistry, the block copolymer is terminated on the end oppositeto the thiol group by a terminal group.

In another aspect, the instant invention relates to methods forimparting a suitable level of lubricity to a biological tissue bycontacting the biological tissue with a sufficient amount of alubricating composition to increase the lubricity of the biologicaltissue. The lubricating composition can be, for example, any of theblock copolymers described above. The biological tissue can be selectedfrom, for example, joints, bone, ocular tissue, nasal tissue, tendons,tendon capsule, and vaginal tissue.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. General representation of an exemplary diblock copolymer of theinvention, with binding block and lubricating block portions identified.

FIG. 2. Graph plotting the coefficient of friction (COF) results forphosphate buffered saline (PBS) solution, the diblock copolymer of FIG.1, the binding block only, and the lubricating block only.

FIG. 3. Graph plotting the COFs of solutions varying in bindingblock:diblock copolymer ratios, as part of a competitive binding study.

FIG. 4. Graph plotting the COFs of the diblock copolymer of FIG. 1 and arandom copolymer version of the diblock copolymer (i.e., same monomericunits but incorporated into the copolymer in random fashion instead ofblock) as synthesized by random RAFT copolymerization of the two blockmonomers, followed by quaternary ammonium conversion.

FIGS. 5A, 5B. FIG. 5A is a graph plotting COF as a function ofconcentration of the diblock copolymer of FIG. 1. FIG. 5B is a graphplotting COF as a function of incubation time, with 1 mg/mL of copolymerfor different durations. The resulting graph can be considered a bindingkinetics curve.

FIGS. 6A, 6B. FIGS. 6A and 6B are graphs plotting the COF of trabecularand subchondral bone samples, respectively, treated with the diblockcopolymer (3) solution (10 mg/mL for 2 hours or 1 mg/mL for 1 hour) orPBS solution.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the invention is directed to block copolymers thatmimic lubricin by having a mucin-like domain and a C-terminalhemopexin-like (PEX-like) domain. The copolymer may, for example,contain a polymer block containing positively or negatively chargedpendant groups and a polymer block containing pendant non-ionichydrophilic groups, particularly hydrophilic groups containing etherand/or hydroxy functional groups. In the case where the pendant group ispolymeric, the copolymer can be further classified as a graft brushcopolymer. The term “copolymer,” as used herein, refers to the presenceof at least two polymer blocks. The copolymer may be, for example, adiblock copolymer, triblock copolymer, tetrablock copolymer, or highercopolymer.

A first class of block copolymers considered herein is encompassed bythe following generic structure:

The substituents R¹, R², and R³ in Formula (1) are independentlyselected from hydrocarbon groups (R) having at least one and up totwelve carbon atoms. The substituents R¹, R², and R³ may, in someembodiments, be more particularly defined as having precisely one, two,three, four, five, six, seven, eight, nine, ten, eleven, or twelvecarbon atoms, or a particular range of carbon atoms therein, e.g., 1-10,1-8, 1-6, 1-4, 1-3, 2-12, 2-10, 2-8, 2-6, 2-4, 3-12, 3-10, 3-8, or 3-6carbon atoms. In some embodiments, R¹, R², and R³ are all the same,while in other embodiments, R¹, R², and R³ are not all the same (or atleast two of R¹, R², and R³ are different). The hydrocarbon group R canbe saturated or unsaturated, straight-chained (linear) or branched, andcyclic or acyclic.

In one set of embodiments, at least one, two, or all of R¹, R², and R³are selected from hydrocarbon groups composed solely of carbon andhydrogen. The hydrocarbon group composed solely of carbon and hydrogencan be, for example, an alkyl, alkenyl, cycloalkyl, cycloalkenyl(aliphatic), or aromatic group. Some examples of straight-chained alkylgroups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl groups.Some examples of branched alkyl groups include isopropyl (2-propyl),isobutyl (2-methylprop-1-yl), sec-butyl (2-butyl), t-butyl, 2-pentyl,3-pentyl, 2-methylbut-1-yl, isopentyl (3-methylbut-1-yl),1,2-dimethylprop-1-yl, 1,1-dimethylprop-1-yl, neopentyl(2,2-dimethylprop-1-yl), 2-hexyl, 3-hexyl, 2-methylpent-1-yl,3-methylpent-1-yl, and isohexyl (4-methylpent-1-yl), wherein the “1-yl”suffix represents the point of attachment of the group. Some examples ofstraight-chained olefinic groups include vinyl, propen-1-yl (allyl),3-buten-1-yl (CH₂═CH—CH₂—CH₂—), 2-buten-1-yl (CH₂—CH═CH—CH₂—),butadienyl, and 4-penten-1-yl groups. Some examples of branched olefinicgroups include propen-2-yl, 3-buten-2-yl (CH₂═CH—CH.—CH₃), 3-buten-3-yl(CH₂═C.—CH₂—CH₃), 4-penten-2-yl, 4-penten-3-yl, 3-penten-2-yl,3-penten-3-yl, and 2,4-pentadien-3-yl, wherein the dot in the foregoingexemplary formulas represents a radical (i.e., the point of attachmentof the group). Some examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.The cycloalkyl group can also be a polycyclic (e.g., bicyclic) group byeither possessing a bond between two ring groups (e.g., dicyclohexyl) ora shared (i.e., fused) side (e.g., decalin and norbornane). Someexamples of cycloalkenyl (aliphatic) groups include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl,cyclooctadienyl, and cyclooctatetraenyl groups. Some examples ofaromatic groups include phenyl and benzyl. The unsaturated cyclichydrocarbon group can also be a polycyclic group (such as a bicyclic ortricyclic polyaromatic group) by either possessing a bond between two ofthe ring groups (e.g., biphenyl) or a shared (i.e., fused) side, as innaphthalene, anthracene, phenanthrene, phenalene, or indene.

In another set of embodiments, at least one of R¹, R², and R³ isselected from hydrocarbon groups containing at least one heteroatom(i.e., non-carbon and non-hydrogen atom), such as one or moreheteroatoms selected from oxygen, nitrogen, sulfur, and halide atoms, aswell as groups containing one or more of these heteroatoms (i.e.,heteroatom-containing groups). In some embodiments, the hydrocarbongroup does not contain hydrogen atoms (e.g., where all hydrogen atomsare replaced with heteroatoms, such as in —CF₃), while in otherembodiments, the hydrocarbon group contains at least one hydrogen atom.Some examples of oxygen-containing groups include hydroxy (OH), alkoxy(OR), carbonyl-containing (e.g., carboxylic acid, ketone, aldehyde,carboxylic ester, amide, and urea functionalities), nitro (NO₂),carbon-oxygen-carbon (ether), sulfonyl, and sulfinyl (i.e., sulfoxide)groups. Some particular examples of alkoxy groups (—OR) include methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, phenoxy,benzyloxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, vinyloxy,and allyloxy groups. In the case of an ether group, the ether group canalso be a polyalkyleneoxide (polyalkyleneglycol) group, such as apolyethyleneoxide group. Some examples of nitrogen-containing groupsinclude primary amine, secondary amine, tertiary amine (i.e., —NR′₂ orNR′₃ ⁺, wherein R′ is independently selected from H and hydrocarbongroups set forth above), nitrile (CN), amide (i.e., —C(O)NR′₂ or—NRC(O)R′, wherein R′ is independently selected from hydrogen atom andhydrocarbon groups set forth above), imine (e.g., —CR′═NR′, wherein R′is independently H or a hydrocarbon group), urea (—NR′—C(O)—NR′₂,wherein R′ is independently H or a hydrocarbon group), and carbamategroups (—NR′—C(O)—OR′, wherein R′ is independently H or a hydrocarbongroup). Some examples of sulfur-containing groups include mercapto(i.e., —SH), thioether (i.e., sulfide, e.g., —SR), disulfide (—R—S—S—R),sulfoxide (—S(O)R), sulfone (—SO₂R), sulfonate (—S(═O)₂OR″, wherein R″is H, a hydrocarbon group, or a cationic group), and sulfate groups(—OS(═O)₂OR″, wherein R″ is H, a hydrocarbon group, or a cationicgroup). Some examples of halide atoms include fluorine, chlorine,bromine, and iodine. One or more of the heteroatoms described above(e.g., oxygen, nitrogen, and/or sulfur atoms) can be inserted betweencarbon atoms (e.g., as —O—, —NR′—, or —S—) in any of the hydrocarbongroups described above. Alternatively, or in addition, one or more ofthe heteroatom-containing groups can replace one or more hydrogen atomson the hydrocarbon group. In some embodiments, any one or more of theabove groups is excluded.

The variables X and X′ in Formula (1) are independently selected from—NR′—, —O—, and a bond, wherein R′ is selected from hydrogen atom andhydrocarbon groups (selected from R groups) having at least one and upto six carbon atoms. In some embodiments, R′ is specifically selectedfrom hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, and t-butyl groups, or a more specific selectionthereof.

In a first instance, the variable Y in Formula (1) is or includes apolyalkylene glycol group. The polyalkylene glycol group can beconveniently expressed by the following structure: (—CR′₂CR′₂O—)_(n)R′,wherein R′ is independently selected from hydrogen atom and hydrocarbongroup (e.g., methyl or ethyl) for each instance of R′, and n is at least2, 3, 4, 5, or 6 and up to, for example, 8, 9, 10, 12, 15, 20, 25, 30,35, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500, or n is within arange bounded by any two of the foregoing values, wherein each of theforegoing values corresponds to the number of alkylene oxide(—CR′₂CR′₂O—) monomer units. In particular embodiments, the polyalkyleneglycol is a polyethylene glycol or polypropylene glycol group. Moreover,the polyalkylene glycol group may or may not be integrated into acopolymer, such as a copolymer containing polyethylene glycol and ananionic polymer portion, such as polyacrylic acid (PAA), polyglutamicacid, or polyaspartic acid.

In a second instance, the variable Y in Formula (1) is or includes asaccharide group. The term “saccharide,” as used herein, includesmonosaccharides (contains one monosaccharide unit) and saccharidescontaining at least or more than two monosaccharide units, such asdisaccharides, trisaccharides, oligosaccharides (e.g., at least 4 and upto 20, 30, 40, 50, or 60 monosaccharide units), and polysaccharides(generally greater than 60, 70, or 80 monosaccharide units, and up to,for example, 100, 200, 300, 400, 500, or 1000 monosaccharide units). Thesaccharide may also be derivatized in such a manner (e.g., esterified,etherified, aminated, or halogenated) that the derivatized version wouldstill reasonably be classified as a saccharide by one skilled in theart. Some examples of monosaccharides include glucose, galactose,fructose, mannose, sialic acid, glucosamine, N-acetylglucosamine, andgalacturonic acid. Some examples of disaccharides include lactose,sucrose, maltose, trehalose, cellobiose, and mannobiose. Some examplesof oligosaccharides include the fructooligosaccharides (FOS),galactooligosaccharides (GOS), and mannanoligosaccharides (MOS). Someexamples of polysaccharides include dextran, dextran sulfate, starch(e.g., amylose or amylopectin), cellulose, hemicellulose, polysialicacid, pectin, glycogen, mannan, galactomannan, xylan, pullulan, xanthan,carrageenan, guar gum, polygalacturonic acid,poly(N-acetylgalactosamine), heparin, hyaluronic acid, and chondroitinsulfate. In some embodiments, the saccharide is selected to have anoverall anionic charge, such as in those saccharides having carboxylicacid, carboxylate, sulfate, or sulfonate groups. The saccharide groupmay or may not be integrated into a copolymer, such as a copolymercontaining an oligosaccharide portion and an oligopeptide or polyacrylicacid portion. In some embodiments, the saccharide-containing copolymercontains a saccharide portion and an anionic polymer portion, such aspolyacrylic acid (PAA), polyglutamic acid, or polyaspartic acid.

In a third instance, the variable Y in Formula (1) is or includes apolyalcohol group. The term “polyalcohol,” as used herein, refers tonon-saccharide groups having a multiplicity (i.e., at least 2, 3, or 4)of hydroxy groups. The polyalcohol may be, for example, a sugar alcoholor polyhydric alcohol. Some examples of sugar alcohols includeerythritol, xylitol, mannitol, glycerol, and sorbitol. The saccharide orpolyalcohol (as Y) is generally attached to the block copolymer ofFormula (1) by one of its hydroxy groups in deprotonated form, whereinX′ can represent the oxygen atom from the group Y; or X′ can represent abond, with Y representing a saccharide or polyalcohol bound by one itsoxygen atoms to the shown C(O) group; or X′ is —NR′—, with Yrepresenting a saccharide or polyalcohol bound by one its carbon atomsto the —NR′— group. In other embodiments, the polyalcohol is a polymerthat contains hydroxy groups. The hydroxy-containing polymer mayinclude, for example, at least 2, 3, 4, 5, or 6 and up to, for example,8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 200, 300,400, or 500 monomer units. Some examples of such polymers includepolyvinylalcohol, poly(hydroxyethylmethacrylate), andpoly(hydroxypropylmethacrylate). The polyalcohol group may or may not beintegrated into a copolymer, such as a polyvinylalcohol-polyacrylic acid(PVA-PAA) copolymer. In some embodiments, the polyalcohol-containingcopolymer contains a polyalcohol portion and an anionic portion, whichmay be an anionic polymer portion, such as polyacrylic acid (PAA),polyglutamic acid, or polyaspartic acid

The subscripts a and b in Formula (1) are independently integers of atleast 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, or 50. Insome embodiments, subscripts a and b are independently no more than 30,40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500,600, 700, 800, 900, 1000, 1200, 1500, 1800, or 2000. In someembodiments, subscript a is selected to be smaller than subscript b. Forexample, subscript a may be within a range of 3-10, 3-20, 3-30, or 3-40while subscript b is within a range of 30-500, 40-500, 50-500, or60-500. In other embodiments, subscript a is selected to be larger thansubscript b. For example, subscript a may be within a range of 30-500,40-500, 50-500, or 60-500 while subscript b is within a range of 3-10,3-20, 3-30, or 3-40.

Subscript c in Formula (1) is an integer of at least 1. In differentembodiments, c is precisely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, orc is within a range bounded by any two of the foregoing values. Thevalue of c corresponds to the number of methylene groups subtended by c.That is, when subscript c is 1, a CH₂ linker is present between X andthe quaternary ammonium group shown in Formula (1); and when subscript cis 2, a CH₂CH₂ linker is present between X and the quaternary ammoniumgroup shown in Formula (1).

Although not shown in Formula (1), the structure depicted in Formula (1)necessarily (i.e., by the laws of chemistry) includes a terminatinggroup on each of the two ends of the copolymer. The terminating group isindependently selected from, for example, hydrogen atom, hydrocarbongroups R, or a heteroatom-containing group, such as —OH, —OCH₃,nitrile-containing alkyl (such as provided by the radical initiator orchain transfer agent), thiol (—SH), or dithioester group (as provided bya RAFT chain transfer agent). In some embodiments, at least one of theterminal groups is a thiol group. The terminating groups oftencorrespond to groups originally present in precursor reactants used tosynthesize the block copolymer, and thus, the type of terminating groupis often dependent on the chemistry used to synthesize the blockcopolymer. Nevertheless, the terminating group may be suitably adjustedby reacting the initially produced block copolymer to append a specificterminating group, e.g., a cartilage binding domain (e.g., apeptide-containing group) which aids in binding the block copolymer to adesired biological tissue. In some embodiments, the cartilage bindingdomain is attached to the block copolymer via an —S— linker, as in theform RS—, where R is the cartilage binding domain. Moreover, althoughalso not shown in Formula (1), the total positive charge of quaternaryammonium groups in the copolymer depicted in Formula (1) iscounterbalanced by a total negative charge of equivalent magnitudeprovided by anions associated with the ammonium groups. The anions maybe selected from any species acceptable for administration into a livingorganism, such as, for example, halides (e.g., chloride, bromide, oriodide), carbonate, bicarbonate, sulfate, bisulfate, bisulfite,carboxylates (e.g., acetate, propionate, butyrate, maleate, andcitrate), mesylate), and sulfonates (e.g., mesylate).

A second class of block copolymers considered herein is encompassed bythe following generic structure:

In Formula (2), the variables X and Y in Formula (2) are defined asprovided above under Formula (1). The variable R is a hydrogen atom,hydrocarbon group (R) having 1-12 carbon atoms (or more particularly, atleast 4, 5, or 6 and up to 7, 8, 9, 10, 11, or 12 carbon atoms), or acartilage binding domain. Where R is a hydrocarbon group having 1-12carbon atoms, the hydrocarbon group may be, more particularly, a linearor branched alkyl or alkenyl group. In some embodiments, the cartilagebinding domain is a peptide-containing group (or “peptide”), which maybe a monopeptide, dipeptide, tripeptide, or oligopeptide containing atleast 4 and up to 5, 6, 7, 8, 9, or 10 peptide units. Thecartilage-binding peptide may be, for example, TKKTLRT (SEQ ID NO: 1),SQNPVQP (SEQ ID NO: 2), WYRGRL (SEQ ID NO: 3), SYIRIADTN (SEQ ID NO: 4)or CQDSETRFY (SEQ ID NO: 5), a cholesterol or other sterol moiety, orany other moiety useful for binding the block copolymer to a biologicaltissue. Conjugation chemistry for attaching cartilage binding domains,hydrophobic alkyl chains, sterols, or other agents to the blockcopolymer are known to those of skill in the art. Although not shown,the structure in Formula (2) necessarily also includes a terminatinggroup opposite to the RS—terminating group. The other terminating groupcan be as described above under Formula (1).

The subscripts d and e in Formula (2) are independently integers of atleast 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, or 50. Insome embodiments, subscripts d and e are independently no more than 30,40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500,600, 700, 800, 900, 1000, 1200, 1500, 1800, or 2000. In someembodiments, subscript d is selected to be smaller than subscript e. Forexample, subscript d may be within a range of 3-10, 3-20, 3-30, or 3-40while subscript e is within a range of 30-500, 40-500, 50-500, or60-500. In other embodiments, subscript d is selected to be larger thansubscript e. For example, subscript d may be within a range of 30-500,40-500, 50-500, or 60-500 while subscript e is within a range of 3-10,3-20, 3-30, or 3-40.

Subscript f in Formula (2) is an integer of at least 1. In differentembodiments, f is precisely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, orf is within a range bounded by any two of the foregoing values. Whensubscript f is 1, a CH₂ linker is present. When subscript f is 2, aCH₂CH₂ linker is present.

In Formula (2), the hydrogen atom on the shown carboxylic acid group maybe (i.e., is optionally) replaced with a positively charged metal ion orpositively charged organic group. Some examples of positively chargedmetal ions include lithium, sodium, and potassium ions. Some examples ofpositively charged organic groups include ammonium ions, such asdimethyl, trimethyl, or tetramethyl ammonium ions.

The block copolymers described above may be synthesized by any suitablepolymerization method. In particular embodiments, the block copolymersare synthesized by reversible addition-fragmentation chain-transfer(RAFT) polymerization, which is well known in the art. In the RAFTprocess, a first polymeric block is produced by reacting a firstfunctionalized vinyl monomer (e.g., 2-(dimethylamino)ethyl acrylate,i.e., DMAEA) with a RAFT transfer agent (e.g., 4-cyanopentanoic aciddithiobenzoate, i.e., CPADB) in the presence of a polymerizationinitiator (e.g., 4,4′-Azobis(4-cyanopentanoic acid), i.e., ACPA). Thefirst polymeric block is then reacted with a second functionalized vinylmonomer (e.g., poly(ethylene glycol) methyl ether acrylate) in thepresence of a polymerization initiator to append a block of polymerizedsecond functionalized vinyl monomer onto the first polymeric block.

The following scheme shows an exemplary RAFT process:

In another aspect, the invention is directed to a pharmaceuticalformulation containing one or more block copolymers of the invention anda pharmaceutically-acceptable carrier (i.e., excipient or diluent). Thepharmaceutical formulation can be prepared for use suitable for avariety of delivery forms, including for intraarticular, intranasal,intravaginal, or ocular delivery. The phrase “pharmaceuticallyacceptable carrier” or equivalent term, as used herein, refers to apharmaceutically acceptable material, composition, or vehicle, which maybe a liquid (diluent or excipient) or solid filler. The phrase“pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication commensurate with areasonable benefit/risk ratio. In the pharmaceutical composition, thecompound is generally dispersed in the physiologically acceptablecarrier, by either being mixed (e.g., in solid form with a solidcarrier) or dissolved or emulsified in a liquid carrier. The carriershould be compatible with the other ingredients of the formulation andphysiologically safe to the subject. Any of the carriers known in theart can be suitable herein depending on the mode of administration. Someexamples of suitable carriers include aqueous solutions, gelatin, fattyacids (e.g., stearic acid) and salts thereof, talc, vegetable fats oroils, gums and glycols, starches, dextrans, and the like.

The pharmaceutical composition can also include one or more auxiliaryagents, such as stabilizers, surfactants, salts, buffering agents,additives, or a combination thereof, all of which are well known in thepharmaceutical arts. The stabilizer can be, for example, anoligosaccharide (e.g., sucrose, trehalose, lactose, or a dextran), asugar alcohol (e.g., mannitol), or a combination thereof. The surfactantcan be any suitable surfactant including, for example, those containingpolyalkylene oxide units (e.g., Tween 20, Tween 80, Pluronic F-68),which are typically included in amounts of from about 0.001% (w/v) toabout 10% (w/v). The salt or buffering agent can be any suitable salt orbuffering agent, such as, for example, sodium chloride, or sodium orpotassium phosphate, respectively. Some examples of additives include,for example, glycerol, benzyl alcohol, and1,1,1-trichloro-2-methyl-2-propanol (e.g., chloretone or chlorobutanol).If required, the pH of the solutions can be suitably adjusted byinclusion of a pH adjusting agent. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners, and the like may be necessary or desirable. Thepharmaceutical formulation may be in the form of a sterile aqueoussolution that contains one or more buffers, diluents, and/or othersuitable additives such as, but not limited to, penetration enhancersand carrier compounds.

In another aspect, the invention is directed to methods for impartinglubricity to a biological tissue, such as to joints, cartilage, andbone, by using the biomimetic copolymers described above under Formulas(1) and (2). In the case of bone, the biomimetic copolymers can reducethe discomfort, pain, and additional damage resulting from directbone-on-bone contact, as sometimes occurs in the advanced stages ofosteoarthritis. In accordance with this method, biological tissue iscontacted with a sufficient (i.e., effective ortherapeutically-effective) amount of any of the copolymer compositionsdescribed above under Formulas (1) and (2) so as to increase thelubricity or to impart a suitable level of lubricity to the biologicaltissue. An increased level of lubricity generally corresponds to a lowerlevel of friction (i.e., frictional coefficient, or coefficient offriction, COF) when the biological tissue slides against the same tissueor other material. Frictional coefficients can be measured using atribometer, which evaluates surface lubrication by linear oscillation ofa sample at variable speeds (generally, 0.1, 0.3, 1, 3, and 10 mm/s) andvariable compressive normal stresses (generally 250 to 300 kPa).

As used herein, the terms “sufficient amount,”“therapeutically-effective amount,” and “effective amount” are usedinterchangeably to refer to an amount of a copolymeric composition ofthe invention that is sufficient to result in sufficient lubricity of abiological tissue, or the prevention of the development, recurrence, oronset of the disease or condition (e.g., osteoarthritis) or one or moresymptoms thereof, or to enhance or improve the prophylactic effect(s) ofanother therapy, reduce the severity and duration of the disease orcondition, ameliorate one or more symptoms of the disease or condition,prevent the advancement of disease or condition, and/or enhance orimprove the therapeutic effect(s) of additional treatment(s).

A therapeutically-effective amount of the block copolymer can beadministered to a patient in one or more doses sufficient to palliate,ameliorate, stabilize, reverse, or slow the progression of the diseaseor condition, or otherwise reduce the pathological consequences of thedisease or condition, or reduce the symptoms of the disease orcondition. The amelioration or reduction need not be permanent, but maybe for a period of time ranging from at least one hour, at least oneday, or at least one week, or more. The effective amount is generallydetermined by the physician on a case-by-case basis and is within theskill of one in the art. Several factors are typically taken intoaccount when determining an appropriate dosage to achieve an effectiveamount. These factors include age, sex and weight of the patient, thecondition being treated, the severity of the condition, as well as theroute of administration, dosage form, regimen, and the desired result.In certain embodiments of the invention, the therapeutically effectiveamount is an amount that is effective to treat osteoarthritis, achievespain relief over a period of time, to improve joint movement andflexibility, to reduce friction in the joint or other acceptedosteoarthritic measure of improvement. In exemplary embodiments, dosagelevels range from about 0.1-10 mg/mL in injection volumes of 0.1-10 mL(for humans), and more typically about 1-5 mg/mL in an injection volumeof 0.1 to 3 mL.

The biological tissue to be lubricated can be contacted with any of theblock copolymers of Formulas (1) or (2) by any of the means well knownin the medical arts. The biological tissue can be contacted with theblock copolymer by, for example, injecting, infusing, implanting,spraying, or coating the block copolymer directly into or onto thebiological tissue, or indirectly into biological tissue surrounding thetissue to be lubricated. In general, contacting a biological tissuemeans that the block copolymer is delivered to the tissue in any mannerthat leads to coating of the surface or bathing of the tissue with thecopolymer. In certain embodiments, the tissue is contacted by injectionor infusion of the composition into a joint space, thereby leading to acoating of cartilage and/or the meniscus found in that joint space.Moreover, the volumes used are at least partly dependent on the type oftissue being contacted, whether a space is being filled, or a surface isbeing coated, as could be determined by one skilled in the medical arts.

In particular embodiments, the block copolymer is injected or infusedinto or onto an arthritic or injured joint or bone to improve thelubricity of the joint or bone. As such, the copolymer provides boundarylubrication. The treatment may be specifically directed for treating orpreventing osteoarthritis. The treatment of osteoarthritis or an injuredjoint, cartilage, or bone preferably results in reduction of symptoms,improved mobility, less joint pain, and overall inhibition of diseaseprogression, or prophylaxis in the case of an injured joint. The methodcan also comprise administering one or more of the block copolymersdescribed above along with simultaneous or sequential administration ofanother composition that functions to augment or work in tandem with theblock copolymer while being outside the scope of Formulas (1) and (2).The augmenting (i.e., auxiliary) composition may be selected from, forexample, hyaluronic acid, lubricin, synovial fluid, glycosaminoglycan,or other auxiliary agent. These other agents can also be administeredby, for example, injection or infusion. In some embodiments, these otheragents may work synergistically with one or more of the block copolymersdescribed above to provide enhanced lubrication and wear protection.

In particular embodiments, the biological tissue is a joint, cartilage,or bone, and more typically, an injured or arthritic joint, cartilage,or bone. In some embodiments, the joint is a weight bearing joint, suchas a hip, knee or ankle joint. Many different joints can benefit from anincreased level of lubricity, including the shoulder, elbow, wrist,hand, finger and toe joints. Nevertheless, the biological tissue beinglubricated is not limited to joints, cartilage, and bone. Otherbiological tissues that may be lubricated by use of the disclosed blockcopolymer include eye tissue, nasal tissue, and vaginal tissue. Thus, byuse of the block copolymers described herein, a variety of conditionsmay be treated beyond those associated with joints, cartilage, and bone.Some of these other conditions include, for example, dry eye syndrome,dry nose, post-menopausal vaginal dryness, carpal tunnel syndrome, andmore. Those skilled in the medical arts can determine the appropriatedelivery route and method for contacting a particular biological tissue.For example, for dry eyes, contacting may be achieved by instillingdrops; for dry nose, contacting may be achieved by nasal spray; forcarpal tunnel syndrome contacting may be achieved by injecting near oraround the inflamed tendon and capsule; and for post-menopausal dryvagina, a pill, troche or suppository can be placed in or implanted inthe vagina. Hence, this method can be used to achieve boundary modelubrication for any of a wide variety of biological tissues that couldbenefit from additional lubrication.

Examples have been set forth below for the purpose of illustration andto describe the best mode of the invention at the present time. However,the scope of this invention is not to be in any way limited by theexamples set forth herein.

Examples Synthesis and Characterization of a Lubricating DiblockCopolymer

In an effort to mimic lubricin's architecture, a diblock copolymer washerein prepared which included a large lubrication block (M_(n)˜200 kDa)mimicking the mucin-like domain of lubricin and a smallcartilage-binding block (M_(n)˜3-10 kDa) mimicking the C-terminusdomain. An exemplary composition showing the two mimicking domains isprovided in FIG. 1. The lubrication domain of the diblock copolymershown in FIG. 1 contains a polyacrylic acid backbone grafted withpolyethylene glycol (PEG) brushes. The foregoing feature aids inhydration and resistance to compression in the polymer. The bindingdomain of the diblock copolymer shown in FIG. 1 contains a polyacrylicacid backbone having pendant quaternary ammonium groups thatnon-specifically interact with negatively-charged cartilage components,such as aggrecan. As further discussed below, applying this polymer tolubricin-deficient bovine articular cartilage resulted in asignificantly reduced coefficient of friction (COF).

Synthesis of the diblock copolymer started with ReversibleAddition-Fragmentation Chain-Transfer (RAFT) polymerization of2-(dimethylamino)ethyl acrylate to synthesize the “pre-binding” block. Asubsequent RAFT polymerization of poly(ethylene glycol) methyl etheracrylate (M_(n) 480) added the lubrication block to the copolymer byusing the “pre-binding” block as the macro-initiator. The tertiaryamines in the “pre-binding” block were then converted into quaternaryammonium groups by treating the block copolymer with an excess of ethylbromide to give the final product (M_(n)˜200 kDa, PDI=1.8). A generalschematic is provided as follows (with R and R′ representing moietiesprovided by the RAFT chain transfer agent):

Synthesis of poly(2-(dimethylamino)ethyl acrylate) (1) with Degree ofPolymerization (DP) of 24

2-(dimethylamino)ethyl acrylate (DMAEA) (4.30 g, 30 mmol) was added to asolution containing 14.0 mg (0.05 mmol) of 4,4′-azobis(4-cyanopentanoicacid) (ACPA), and 139.5 mg (0.5 mmol) of 4-cyanopentanoic aciddithiobenzoate (CPADB) in 5 mL of anisole. The mixture was deoxygenatedby five freeze-thaw cycles before it was heated up to 70° C. for 48hours. The reaction was then quenched by liquid nitrogen freezing, andthe residue was purified by inducing precipitation by addition of hexane(repeated five times). The structure of the purified product wasconfirmed by ¹H NMR to have the foregoing structure:

Synthesis of Block Copolymer (2) by Appending a PEG Block onto (1)

PEG(9)-acrylate, methoxy-terminated (3.46 g, 7.2 mmol) was added to asolution containing 30.9 mg (0.009 mmol) of (1) and 0.5 mg (0.0018 mmol)of ACPA in 6 mL of anisole. The mixture was deoxygenated by fivefreeze-thaw cycles before it was heated up to 65° C. for 8 hours. Thereaction was then quenched by liquid nitrogen freezing, and the residuewas purified by inducing precipitation by addition of hexane (repeatedfive times). The structure of the purified product was confirmed by ¹HNMR and GPC to have the following structure:

Synthesis of Quaternary Ammonium Derivative (3) of Block Copolymer (2)

0.3 mL of ethyl bromide was added dropwise into a solution containing865.9 mg of (2) in 3 mL of acetone at 0° C. The mixture was stirred for48 hours at room temperature and was then quenched by evaporating thesolvent with a nitrogen flow. The residue was dissolved in methylenechloride, and the product was initially purified by inducingprecipitation by addition of hexane (repeated five times). The product(3) was then dissolved in 0.01 M PBS (phosphate buffered saline)solution and further purified by dialysis in 0.01 M PBS for 24 hours anddeionized water for an additional 48 hours before lyophilization. Thestructure of the purified product (3) was confirmed by ¹H NMR and GPC tohave the following structure:

Evaluation of Lubricating Ability of Block Copolymer (3) on Cartilage

To evaluate the diblock copolymer (3) as a synthetic lubricant, thetribological behavior of the copolymer was assessed using a custom-builtcartilage-on-glass tribometer (Gleghorn, J. P. et al., J. Orthop. Res.2009, 27 (6), 77). Cartilage samples were obtained from thepatellofemoral groove of neonatal bovine stifles and incubated in 1.5 MNaCl to remove lubricin. Samples were incubated in PBS and then inpolymer solution for 120 minutes to saturate the cartilage surface.After incubation, samples were loaded onto the tribometer in a PBS bathunder boundary mode conditions (30% compressive strain and linearoscillation speeds of 0.3 mm/s). To demonstrate the importance of thediblock architecture, individual blocks as binding block only andlubrication block only were also tested under the same condition. FIG. 2is a graph plotting the coefficient of friction (COF) results for PBS,the diblock copolymer (3), the binding block only, and the lubricationblock only. In vitro boundary lubrication testing resulted in a decreasein COF from 0.391±0.020 to 0.088±0.039 (n=4-11, *p<0.0001), which iscomparable to the results of lubricin-treated groups (dashed line inFIG. 2, with COF=0.093±0.011)(Gleghorn et al., supra). Notably, asimilar trend of decreased COF was not observed with treatment usingeither of the individual blocks, which suggests that both the bindingand lubricating block are needed for boundary lubrication of articularcartilage.

The importance of the binding block for lubrication was furtherdemonstrated by a competitive binding study. COFs of cartilages sampleswere characterized after exposure to solutions composed of combinationsof the binding domain and diblock copolymer in molar ratios of bindingblock:diblock copolymer ranging from 100:1 to 1:1. FIG. 3 is a graphplotting the COFs of solutions varying in binding block:diblockcopolymer (3) ratios. As indicated by the data in FIG. 3, COFs of thesamples exhibited dose-response behavior. As expected, highconcentrations of the binding domain effectively inhibited lubricationby the diblock copolymer, which suggests that efficiently binding thepolymers on the surface is crucial to their success in effectivelylubricating cartilage. As shown in FIG. 3, the behavior follows asigmoidal dose-response (R²=0.87, IC₅₀=13.45, n=4-6).

In another experiment, a random copolymer version of the diblockcopolymer (i.e., same monomeric units but incorporated into thecopolymer in random fashion instead of block) was synthesized by randomRAFT copolymerization of the two monomers, followed by quaternaryammonium conversion. FIG. 4 is a graph plotting the COFs (using the samemethod of tribological testing as described above) of the diblockcopolymer (3) and random polymer version. Notably, as indicated by theresults in FIG. 4, the random copolymer was significantly less capablein lubricating articular cartilage than the block copolymer. The failureof the random polymer to lubricate the articular cartilage in the sametest confirmed the importance of the binding block for providing thesignificantly improved lubrication ability. In the boundary lubricationmode, frictional properties are primarily governed by solid-solidinteractions, and therefore, are largely dependent on the physical andchemical properties of the opposing surfaces. It is critical for theboundary mode lubricant to form a molecular layer that effectively coatsthe cartilage surface to support the normal load. Individualpositively-charged quaternary ammonium groups that are randomlydistributed in the polymer backbone are not able to efficiently interactwith the cartilage surface, which again, demonstrates the importance ofthe diblock structure.

Next, some key lubrication parameters of the diblock copolymer wereevaluated and compared to natural lubricin. Briefly, a dosing study wasperformed using cartilage samples that were treated with solutions of(3) ranging in concentration from 0.01 to 10 mg/mL. FIG. 5A is a graphplotting COF as a function of concentration of the diblock copolymer(3). As indicated by FIG. 5A, the COF of samples exhibited adose-responsive behavior (R²=0.89) in which high concentrations ofcopolymer (3) result in effective lubrication of the cartilage(EC₅₀=0.404 mg/ml) at a level that is comparable to lubricin (EC₅₀ isgreater than 0.030 mg/mL under similar conditions). FIG. 5B is a graphplotting COF as a function of incubation time, with 1 mg/mL of diblockcopolymer (3) for different durations. The resulting graph can beconsidered a binding kinetics curve. The concentration was selectedusing the inflection point of the sigmoidal dosing curve. When fittinginto a one-phase decay followed by plateau model (R²=0.95), the bindingkinetic curve (FIG. 5B) revealed a binding time constant (τ) of 7.19minutes, which is comparable to that of natural lubricin (˜9 minutes),e.g., Gleghorn et al., supra.

The above results demonstrate the successful design of a diblockcopolymer whose architecture mimicks the lubricating protein lubricin.Evaluated by a custom tribometer, block copolymer (3) successfullyreduced the coefficient of friction of articular cartilage in theboundary mode (0.088±0.039) to a level that is equivalent to naturallubricin (0.093±0.011). Additionally, both the EC₅₀ (0.404 mg/mL) andbinding time constant (7.19 minutes) of this polymer are comparable tothe corresponding parameter of lubricin (>0.03 mg/mL, ˜9 minutes). Likelubricin, the outstanding tribological properties of this diblockcopolymer can be explained by its molecular architecture. Particularly,efficient binding of this polymer on articular cartilage has been shownto be essential to effective lubrication. The block copolymer (3) hasunexpectedly been shown to possess at least the lubrication ability oflubricin, which indicates a significant clinical potential.

Evaluation of Lubricating Ability of Block Copolymer (3) on Bone

In this study, the same block copolymer (3) was tested for itslubricating ability on bone. Bone samples were obtained from the femoralcondyle of neonatal bovine stifles. The bone plugs were extracted by a 6mm diameter drill through the cartilage layer to the growth plate andtrimmed to 2 mm in height. The subchondral surface was exposed byremoving the cartilage layer, and the trabecular bone plugs wereobtained by cutting the medial part of the drilled bone plugs. Bonesamples were incubated in PBS solution and then the polymer solutioncontaining (3) (10 mg/mL for 2 hours or 1 mg/mL for 1 hour). Thetribological properties were measured on a custom bone-on-glasstribometer (Gleghorn et al., supra) under 450 g normal load and linearoscillation speeds of 0.3, 1, and 3 mm/s. Coefficient of friction wascalculated as the average shear force while sliding divided by thenormal force. One-way ANOVA and Student's t-test with matched slidingspeeds were used to determine the mathematical significance betweentreatments.

It is well known that the coefficients of friction (COF) of bothtrabecular and subchondral bones are significantly elevated incomparison to cartilage under the same conditions. FIGS. 6A and 6B aregraphs plotting the COF of trabecular and subchondral bone samples,respectively, treated with the diblock copolymer (3) solution (10 mg/mLfor 2 hours or 1 mg/mL for 1 hour) or PBS solution. The COF of cartilagein PBS in boundary mode or in synovial fluid is also shown. As shown bythe data in FIGS. 6A and 6B, bone plug samples incubated in polymersolution exhibited COFs significantly lower than PBS controls (ΔCOF˜−0.2for trabecular bone, p<0.05; ΔCOF˜−0.15 for subchondral bone, p<0.05).As can also be ascertained by the data in FIGS. 6A and 6B, thelubrication is more improved using a higher concentration (e.g., above 1mg/mL, or at least 2, 5, or 10 mg/mL) of polymer solution and/or longerincubation time (e.g., more than 1 hour, or at least 1.5 or 2 hours).The results demonstrate that the block copolymers described herein caneffectively lubricate cartilage or bone to a level that is comparable oreven superior to the COF of cartilage in PBS in the boundary mode.Without being bound by theory, it is believed that the diblockcopolymers of the invention strongly interact with negatively chargedcartilage or bone mineral components and resist normal compression byvirtue of the bottle-brush type of architecture.

While there have been shown and described what are at present consideredthe preferred embodiments of the invention, those skilled in the art maymake various changes and modifications which remain within the scope ofthe invention defined by the appended claims.

What is claimed is:
 1. A block copolymer having the following structure:

wherein: R¹, R², and R³ are independently selected from hydrocarbongroups having at least one and up to twelve carbon atoms; X and X′ areindependently selected from —NR′—, —O—, and a bond, wherein R′ isselected from hydrogen atom and hydrocarbon groups having at least oneand up to six carbon atoms; Y is a polyalkylene glycol; subscript a isan integer in a range of 3-40; subscript b is an integer in a range of30-500; and subscript c is an integer of at least 1; wherein, by thelaws of chemistry, the block copolymer is terminated on each end byterminal groups, and the total positive charge of quaternary ammoniumgroups in the copolymer is counterbalanced by a total negative charge ofequivalent magnitude provided by anions associated with said ammoniumgroups.
 2. The block copolymer of claim 1, wherein said polyalkyleneglycol is polyethylene glycol.
 3. The block copolymer of claim 1,wherein said polyalkylene glycol is constructed of at least two and upto 500 monomer units.
 4. The block copolymer of claim 1, wherein saidpolyalkylene glycol is constructed of at least two and up to 200 monomerunits.
 5. The block copolymer of claim 1, wherein said polyalkyleneglycol is constructed of at least two and up to 100 monomer units. 6.The block copolymer of claim 1, wherein said polyalkylene glycol isconstructed of at least two and up to 20 monomer units.
 7. The blockcopolymer of claim 1, wherein R¹, R², and R³ are independently selectedfrom alkyl groups having at least one and up to twelve carbon atoms. 8.The block copolymer of claim 1, wherein at least one of said terminalgroups is a thiol group.
 9. A method for imparting increased lubricityto a biological tissue, the method comprising contacting said biologicaltissue with a sufficient amount of a composition to impart increaselubricity, said composition comprising a block copolymer having thefollowing structure:

wherein: R¹, R², and R³ are independently selected from hydrocarbongroups having at least one and up to twelve carbon atoms; X and X′ areindependently selected from —NR′—, —O—, and a bond, wherein R′ isselected from hydrogen atom and hydrocarbon groups having at least oneand up to six carbon atoms; Y is a polyalkylene glycol; subscript a isan integer in a range of 3-40; subscript b is an integer in a range of30-500; and subscript c is an integer of at least 1; wherein, by thelaws of chemistry, the block copolymer is terminated on each end byterminal groups, and the total positive charge of quaternary ammoniumgroups in the copolymer is counterbalanced by a total negative charge ofequivalent magnitude provided by anions associated with said ammoniumgroups.
 10. The method of claim 9, wherein at least one of said terminalgroups is a thiol group.
 11. The method of claim 9, wherein saidbiological tissue is selected from joints, bone, ocular tissue, nasaltissue, tendons, tendon capsule, and vaginal tissue.
 12. A blockcopolymer having the following structure:

wherein: R¹, R², and R³ are independently selected from hydrocarbongroups having at least one and up to twelve carbon atoms; X and X′ areindependently selected from —NR′—, —O—, and a bond, wherein R′ isselected from hydrogen atom and hydrocarbon groups having at least oneand up to six carbon atoms; Y is selected from polyalkylene glycol,saccharide, and polyalcohol; subscript a is an integer in a range of3-40; subscript b is an integer in a range of 30-500; and subscript c isan integer of at least 1; wherein, by the laws of chemistry, the blockcopolymer is terminated on each end by terminal groups, wherein at leastone of said terminal groups is a thiol group, and the total positivecharge of quaternary ammonium groups in the copolymer is counterbalancedby a total negative charge of equivalent magnitude provided by anionsassociated with said ammonium groups.